Gastro-electric stimulation for reducing the acidity of gastric secretions or reducing the amounts thereof

ABSTRACT

A gastro-electric stimulation system comprises a INS for producing a electrical stimulation signal, at least one medical electrical lead, and at least two electrical contacts. The medical electrical lead has a proximal end and a distal end, the proximal end being connected to the INS, the distal end being adapted for placement in or near a patient&#39;s stomach or appropriate nerve or nerve portion. The electrodes are disposed near the distal end of the medical electrical lead, and are The electrodes are electrically connected through the medical electrical lead to the INS to receive the electrical stimulation signal and convey such signal to the selected electrode implant position. The electrical stimulation signal is provided in an amount and manner adapted to decrease the pH of the gastric acid in the patient&#39;s stomach and/or to decrease the amount of gastric acid produced thereby.

RELATED APPLICATIONS

[0001] This application hereby incorporates by reference herein in theirrespective entireties U.S. patent application Ser. No. ______ toDinsmoor et al. entitled “Gastro-Electric Stimulation for Increasing theAcidity of Gastric Secretions or Increasing the Amounts Thereof” andU.S. patent application Ser. No. ______ to Starkebaum et al. entitled“Gastric Electric Stimulation for Treatment of Gastro-Esophageal RefluxDisease,” such applications being filed on even date herewith.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to medical devices used toelectrically stimulate the digestive system, and more specifically todevices employed to electrically stimulate portions of the digestivesystem and/or the vagus nerve to reduce the acidity of gastric acidsecretions and/or reduce the amount of gastric acid secretions producedby the stomach.

[0003] The medical device industry produces a wide variety of electronicand mechanical devices for treating patient medical conditions.Depending upon a patient's medical condition, medical devices may besurgically implanted or connected externally to the patient. Physiciansuse medical devices alone or in combination with drug therapies andsurgery to treat patient medical conditions. For some medicalconditions, medical devices provide the best, and sometimes the only,therapy to treat a medical condition and restore an individual to a morehealthful condition and a fuller life. One type of medical deviceapplied to treat conditions receptive to neurological therapy is animplantable neurostimulator (hereafter “INS”). An INS applies anelectrical signal to the nervous system to create a response such asreducing patient pain or influencing a body organ, and may also beemployed to apply an electrical signal to the enteric nervous system.

[0004] The digestive system is composed of the digestive tract,accessory organs and the enteric nervous system, and functions toprepare food for absorption and use by the body. The enteric nervoussystem is the digestive system's nervous system, and it functions toboth receive and transmit information. This system receives neurologicalinformation from the digestive system through afferent nerves, andissues instructions through efferent nerves. Gastric myoelectricalactivity is described by Kenneth Koch et al. in Electrogastrography, “AnIllustrated Guide To Gastrointestinal Motility,” 2^(nd) Ed., pp. 290-307(1993). The vagus nerve contains both afferent and efferent nerves andprovides nervous system connectivity between digestive system organs,including between the stomach and brain. The gastric frequency of apatient is generally about 3.0 cycles per minute. The enteric nervoussystem is believed to exert some control over gastric acid secretionfunctions.

[0005] Previous drug-based treatments for lowering the acidity ofgastric acid do not satisfactorily treat some patient conditions, andmoreover may suffer from a variety of undesirable side effects,especially when used over long periods of time. Pharmaceutical productsaimed at reducing gastric secretion acidity such as NEXIUM®, PREVACID®,ZANTAC®, PROTONIX® may have wide-ranging systemic effects, such asmotility disorders, allergic reactions and diarrhea. Additionally,because of the systemic manner in which they affect the human organism,the treatment provided by and the various side effects produced bypharmaceutical products cannot be terminated instantaneously, butinstead must be allowed to run their course until metabolized orotherwise eliminated by the body. Previous treatments employingelectrical stimulation techniques have not applied stimulation tocertain areas of the patient's digestive system for the purpose oflowering the acidity of gastric secretions, or for the purpose oflowering the amount of gastric secretions produced.

[0006] The gastrointestinal tract has an extensive nervous system of itsown called the enteric nervous system. There are two main plexuses inthe enteric system:

[0007] (1) An outer plexus-called the myenteric plexus-that lies betweenthe longitudinal and circular muscle layers, and;

[0008] (2) An inner plexus-called the submucosal plexus-that lies in thesubmucosa.

[0009] The myenteric plexus primarily controls the gastrointestinalmovements, and the submucosal plexus mainly controls gastrointestinalsecretion and local blood flow. The sympathetic and parasympatheticfibers connect with both the plexuses, and can further activate orinhibit gastrointestinal function (see FIG. 5a).

[0010] More than a dozen neurotransmitters have been identified in thegastrointestinal tract. Acetylcholine (a parasympatheticneurotransmitter) typically excites gastrointestinal activity andnorepinephrine (a sympathetic neurotransmitter) typically inhibitsgastrointestinal activity.

[0011] The cranial parasympathetic fibers extensively innervate thestomach, and are transmitted almost entirely in the vagus nerves thatrun proximal to the esophagus. The sympathetic fibers to thegastrointestinal tract originate in the spinal cord between segments T-5and L-2. Stimulation of these fibers result in an inhibitory effect bynorepinephrine which can block movement of food through thegastrointestinal tract.

[0012] Many afferent sensory nerve fibers arise in the gut. These nervescan be stimulated by (1) irritation of the gut mucosa, (2) excessivedistention of the gut, or (3) presence of specific chemical substancesin the gut. Almost 80% of nerve fibers in the vagus bundle are afferentrather than efferent. These fibers transmit afferent signals into themedulla, which in turn initiates many reflex signals that controlgastrointestinal functions. As such, stimulation of the vagus nerve maydirectly affect the gastro-intestinal tract through efferent nervecapture or through a more circuitous route involving the medulla.

[0013] As shown in FIG. 5b, the wall of the stomach is lined withbillions of single-cell mucous glands. These cells extrude mucousdirectly onto the epithelial surface to act as a lubricant and preventauto-digestion. There are also two types of tubular glands that exist,the oxyntic glands and the pyloric glands. The oxyntic glands secretehydrochloric acid (HCl) and the pyloric glands secrete the hormonegastrin. The oxyntic glands are located on the inside surfaces of thebody and fundus of the stomach, and the pyloric glands are located inthe antral portion of the stomach. Gastrin and histamine are potentstimulants for acid release by the parietal cells in the oxyntic glands;the parietal cells secrete a highly acidic solution that contains about160 millimoles of HCl per liter. A synthetic form of gastrin known aspentagastrin is composed of the terminal four amino acids of naturalgastrin plus the amino acid alanine. It has all the same physiologicalproperties as natural gastrin.

[0014] It has been shown that relatively slow stimulation of the vagi(4-8 Hz) induces maximal acid secretion in cats (Sjodin, 1975).Pharmaceutical companies frequently use this model to testacid-suppressing drugs. Grundy and Scratcherd, however, found thathigher rate electrical stimulation (120 Hz) of the vagus nervesignificantly reduced acid production versus basal output in ferrets. Intheir experiment, they performed a bilateral vagotomy in the neck andstimulated the thoracic vagi via a left thoracotomy. The stimulationregime they applied was “physiologic” (a taped replica of natural vagalactivity), “burst” (60 or 120 Hz, 500 microsecond pulse width), or“continuous” (6 Hz). Their data showed that continuous low-ratestimulation increased acid output relative to the “taped” physiologicstimulation, while burst stimulation significantly decreased acidoutput.

[0015] Some prior art publications relating to the present invention areas follows:

[0016] Kenneth Koch et al., “An Illustrated Guide To GastrointestinalMotility,” Electrogastrography, 2nd Ed., pp. 290-307 (1993).

[0017] Kenneth Koch et al., “Functional Disorders of the Stomach,”Seminars in Gastrointestinal Disease, Vol. 7, No. 4, 185-195 (October1996).

[0018] Kenneth Koch, “Gastroparesis: Diagnosis and Management,”Practical Gastroenterology (November 1997).

[0019] Babajide Familoni et al., “Efficacy of Electrical Stimulation atFrequencies Higher than Basal Rate in Mayine Stomach,” DigestiveDiseases and Sciences, Vol. 42, No. 5 (May 1997).

[0020] Babajide O. Familoni, “Electrical Stimulation at a FrequencyHigher than Basal Rate in Human Stomach,” Digestive Diseases andSciences, Vol. 42, No. 5 (May 1997).

[0021] Grundy, D. and Scratcherd, T., “Effects of stimulation of thevagus nerve in bursts on gastric acid secretion and motility in theanaesthetized ferret,” J. Physiol., 333: 451-461, 1982.

[0022] Sasaki, N., et al., “Selective action of a CCK-B/gastrin receptorantagonist, S-0509, on pentagastrin-, peptone meal- and beer-stimulatedgastric acid secretion in dogs,” Aliment. Pharmacol. Ther., 14: 479-488,2000.

[0023] Sjodin, L., “Gastric acid responses to graded vagal stimulationin the anaesthetized cat,” Digestion, 12(1): 17-24, 1975.

[0024] Physician's Manual, NeuroCyberonics Prosthesis, Bipolar Lead,Model 300, September, 2001.

[0025] U.S. Pat. No. 5,188,104 to Wernicke et al. for “Treatment ofEating Disorders by Nerve Stimulation.”

[0026] U.S. Pat. No. 5,231,988 to Wernicke et al. for “Treatment ofEndocrine Disorders by Nerve Stimulation.”

[0027] U.S. Pat. No. 5,263,480 to Wernicke et al. for “Treatment ofEating Disorders by Nerve Stimulation.”

[0028] U.S. Pat. No. 5,292,344 to Douglas for “Percutaneously placedelectrical gastrointestinal pacemaker INSy system, sensing system, andpH monitoring system, with optional delivery port.”

[0029] U.S. Pat. No. 5,423,872 to Cigaina for “Process and Device forTreating Obesity and Syndrome Motor Disorders of the Stomach of aPatient.”

[0030] U.S. Pat. No. 5,540,730 to Terry for “Treatment of motilitydisorders by nerve stimulation.”

[0031] U.S. Pat. No. 5,690,691 to Chen for “Gastro-intestinal pacemakerhaving phased multi-point stimulation.”

[0032] U.S. Pat. No. 5,716,385 to Mittal for “Crural diaphragm pacemakerand method for treating esophageal reflux disease.”

[0033] U.S. Pat. No. 5,836,994 to Bourgeois for “Method and apparatusfor electrical stimulation of the gastrointestinal tract.”

[0034] U.S. Pat. No. 5,925,070 to King et al. for “Techniques foradjusting the locus of excitation of electrically excitable tissue.”

[0035] U.S. Pat. No. 5,941,906 to Barreras et al. for “Implantable,modular tissue INS.”

[0036] U.S. Pat. No. 6,083,249 to Familoni for “Apparatus for sensingand stimulating gastrointestinal tract on-demand”

[0037] U.S. Pat. No. 6,097,984 to Douglas for “System and method ofstimulation for treating gastro-esophageal reflux disease.”

[0038] U.S. Pat. No. 6,238,423 to Bardy for “Apparatus and method fortreating chronic constipation.”

[0039] U.S. Pat. No. 6,381,496 to Meadows et al. for “Parameter contextswitching for an implanted device.”

[0040] U.S. Pat. No. 6,393,325 to Mann et al. for “Directionalprogramming for implantable electrode arrays.”

[0041] U.S. Pat. No. 6,449,511 to Mintchev for “Gastrointestinalelectrical INS having a variable electrical stimulus.”

[0042] U.S. Pat. No. 6,453,199 to Kobosev for “ElectricalGastro-Intestinal Tract INS.”

[0043] U.S. Pat. No. 6,516,227 to Meadows et al. for “Rechargeablespinal cord INS system.”

[0044] U.S. Patent Application Publication No. 2002 165589 for “GastricTreatment and Diagnosis Device and Method.”

[0045] U.S. Patent Application Publication No. 2003 014086 for “Methodand Apparatus for Electrical Stimulation of the Lower EsophagealSphincter.”

[0046] U.S. Patent Application Publication No. 2002 116030 for“Electrical stimulation of the Sympathetic Nerve Chain.”

[0047] U.S. Patent Application Publication No. 2002 193842 for“Heartburn and Reflux Disease Treatment Apparatus.”

[0048] U.S. Patent Application Publication No. 2002 103424 for“Implantable Medical Device Affixed Internally within theGastrointestinal Tract.”

[0049] U.S. Patent Application Publication No. 2002 198470 for “Capsuleand Method for Treating or Diagnosing the Intestinal Tract.”

[0050] PCT Patent Application WO 0089655 for “Sub-Mucosal GastricImplant Device and Method.”

[0051] PCT Patent Application WO 0176690 for “GastrointestinalElectrical Stimulation.”

[0052] PCT Patent Application WO 02087657 for “Gastric Device andSuction Assisted Method for Implanting a Device on a Stomach Wall.”

[0053] PCT Patent Application WO 0238217 for “Implantable NeuromuscularINS for Gastrointestinal Disorders.”

[0054] All patents and technical papers listed hereinabove are herebyincorporated by reference herein, each in its respective entirety. Asthose of ordinary skill in the art will appreciate readily upon readingthe Summary of the Invention, Detailed Description of the PreferredEmbodiments and claims set forth below, at least some of the devices andmethods disclosed in the patents and publications listed hereinabove maybe modified advantageously in accordance with the teachings of thepresent invention. The foregoing and other objects, features andadvantages, which will now become more readily apparent by referring tothe following specification, drawings and claims, are provided by thevarious embodiments of the present invention.

SUMMARY OF THE INVENTION

[0055] The present invention has certain objects. That is, variousembodiments of the present invention provide solutions to one or moreproblems existing in the prior art respecting conventional treatment forgastric hyperacidity or excessive gastric acid production in a patient,including one or more of: (a) sequelae or side-effects resulting fromthe administration of pharmaceutical products; (b) the requirement topurchase expensive pharmaceutical products on an on-going basis; (c)when administering pharmaceutical products, not having the ability toterminate or change instantaneously administration of the therapy; and(d) lack of positive response to the administration of pharmaceuticaltherapy.

[0056] Various embodiments of the present invention have certainadvantages, including one or more of: (a) targeted delivery of therapy;(b) ability to change the therapy delivered on-demand orinstantaneously; (c) multiple methods of feedback control for optimizingtherapy (e.g., pH, sensed blood metabolite levels, patient activated,time-dependent (e.g., activate stimulation therapy at mealtime); (d)lower cost than pharmaceuticals; (e) potential for the delivery ofsuperior therapy; and (f) the patient does not have to remember to takea drug daily or according to a daily regimen.

[0057] Various embodiments of the present invention have certainfeatures, including, but not limited to, the following: One or moreelectrical stimulation signals are applied to one or more appropriateportions of a patient's digestive system, vagus nerve, and/or portionsin the vicinity of either in an amount and manner effective to lower theamount of a patient's gastric acid secretions and/or to lower theacidity of such secretions. The at least one electrical stimulationsignal is applied by an INS that has at least one medical electricallead positionable, secured or attached to or in a patient's digestivesystem and/or vagus nerve, or in the vicinity thereof. Each such leadcarries at least one electrode, and preferably at least two electrodes,positionable or attachable for contact with or in proximity to thepatient's digestive system or vagus nerve. In one embodiment of thepresent invention, the electrical stimulation signal is adapted toreduce the amount or frequency of gastric acid secretions. In anotherembodiment of the present invention, the electrical stimulation signalis adapted to reduce the acidity of gastric secretions.

BRIEF DESCRIPTION OF THE DRAWINGS

[0058] These and other objects, features and advantages of the presentinvention will be more readily understood from the following detaileddescription of the preferred embodiments thereof, when considered inconjunction with the drawings, in which like reference numerals indicateidentical structures throughout the several views, and wherein:

[0059]FIG. 1a illustrates one suitable arrangement for implanting oneembodiment of a gastro-electric stimulation system of the presentinvention;

[0060]FIG. 1b shows illustrative components of one embodiment of agastro-electric stimulation system of the present invention;

[0061]FIG. 1c shows an illustrative INS and associated medicalelectrical leads according to one embodiment of the present invention;

[0062]FIG. 2a shows a block diagram of one embodiment of an open-loopgastro-electric stimulation system of the present invention;

[0063]FIG. 2b shows a block diagram of one closed-loop embodiment of agastro-electric stimulation system of the present invention;

[0064]FIG. 2c shows a block diagram of another embodiment of a closedloop gastro-electric stimulation system of the present invention;

[0065]FIG. 2d shows a signal amplitude vs. time chart obtained inaccordance with the present invention;

[0066]FIG. 3 shows a block diagram of one embodiment of the presentinvention;

[0067]FIG. 4a shows one embodiment of a gastrointestinal stimulationsystem of the present invention;

[0068]FIGS. 4b through 4 f illustrate various embodiments of medicalelectrical leads suitable for use in the system of the presentinvention;

[0069]FIGS. 5a through 5 d illustrate cross-sectional views of variousportions of a patient's gastrointestinal tract and the nerve innervationand acid-production sites associated therewith;

[0070]FIGS. 6a through 6 f illustrate various electrode locations in ornear the stomach and/or vagus nerve of a patient that may be stimulatedand/or sensed in accordance with several embodiments of the presentinvention;

[0071]FIG. 7 illustrates various locations in or near the stomach and/orvagus nerve of a patient for feedback control sensors according to someembodiments of closed-loop feedback control systems of the presentinvention;

[0072]FIGS. 8a through 8 c illustrate stimulation pulse, regime andcontrol parameters according to some embodiments of the presentinvention;

[0073]FIG. 9 illustrates several methods of stimulating a patient'sstomach and/or vagus nerve so as to lower the amount of gastric acidsecretions and/or to lower the acidity of such secretions in a patient;and

[0074]FIG. 10 shows test data obtained in accordance with one embodimentof the present invention.

[0075] The drawings are not necessarily to scale. Like numbers refer tolike parts or steps throughout the drawings.

DETAILED DESCRIPTIONS OF EXEMPLARY EMBODIMENTS OF THE PRESENT INVENTION

[0076] In the following descriptions of the preferred embodiments,reference is made to the accompanying drawings that form a part hereof,and in which are shown by way of illustration several specificembodiments of the invention. It is to be understood that otherembodiments of the present invention are contemplated and may be madewithout departing from the scope or spirit of the present invention. Thefollowing detailed description, therefore, is not to be taken in alimiting sense. Instead, the scope of the present invention is to bedefined in accordance with the appended claims.

[0077] In the present invention, electrical stimulation of appropriateportions of the vagus nerve and/or the digestive system, more aboutwhich we say below, influences the amount and/or frequency of gastricacid secretions, and may also be employed to reduce the acidity of suchsecretions, leading to an overall increase in the pH of the gastric acidcontained in a patient's stomach. Nerve impulses generated by electricalstimulation of appropriate portions of the vagus nerve and/or digestivesystem travel by means of both afferent and efferent pathways to cellsin stomach lining which produce gastric acid. Some impulses may travelfrom the digestive system along a vagal afferent pathway to the brainand then along a vagal efferent pathway from the brain to the stomachlining. Various portions of the stomach in the digestive system are wellsuited for stimulation in accordance with some embodiments of thepresent invention. For example, the wall of the stomach is suitable formaking electrical connections and the stomach is well innervated by thevagus nerve, and the stomach pacemaker region is particularly wellinnervated by the vagus nerve and other portions of the digestivesystem.

[0078]FIG. 1 further shows one embodiment of INS 10 of the presentinvention having a lead positioned near a desired or target nerve ornerve portion 8. INS 10 shown in FIG. 1 is a implantable electricalstimulator comprising at least one implantable medical electrical lead16 attached to hermetically sealed enclosure 14, lead 16 being implantednear desired or target nerve or nerve portion 8. Enclosure 14 is formedof a biocompatible material such as an appropriate metal alloycontaining titanium. It is important to note that at least one more lead18 (not shown in the drawings) may be employed in accordance withcertain embodiments of the present invention, where multiple nervetarget sites or portions are to be stimulated simultaneously orsequentially and/or where such multiple target sites or portions areincapable of being stimulated, or are difficult to stimulate, using asingle lead even if the single lead contains multiple stimulationelectrodes or arrays of stimulation electrodes. FIG. 1c shows anillustrative INS and associated medical electrical leads according toone embodiment of the present invention.

[0079] Referring now to FIG. 1b and FIGS. 4a through 4 f, lead 16provides electrical stimulation pulses to the desired nerve target sitesor portions and thereby inhibits or excites signals originating in orcarried by a desired or target nerve or nerve portion located in thevicinity of the electrode(s) thereof. Leads 16 and lead 18 may haveunipolar electrodes disposed thereon (where enclosure 14 is employed asan indifferent electrode) or may have bipolar electrodes disposedthereon, where one or more electrodes disposed on a lead are employed asthe indifferent electrode. In one embodiment of the present invention,lead 16 extends from lead connector 13, which in turn forms an integralportion of lead extension 15 connected at its proximal end to connectorheader module 12.

[0080] Leads 16 and 18 are preferably less than about 5 mm in diameter,and most preferably less than about 1.5 mm in diameter. Polyurethane isa preferred material for forming the lead body of leads 16 and 18,although other materials such as silicone may be employed. Electricalconductors extending between the proximal and distal ends of leads 16and 18 for supplying electrical current to the electrodes are preferablyformed of coiled, braided or stranded wires comprising an MP35Nplatinum-iridium alloy. Electrodes 20, 21, 22 and 23 may be ringelectrodes, coiled electrodes, electrodes formed from portions of wire,barbs, hooks, spherically-shaped members, helically-shaped members, ormay assume any of a number of different structural configurations wellknown in the art.

[0081] Inter-electrode distances on leads 16 and 18 are preferably about3 mm, but other inter-electrode distances may be employed such as about1 mm, about 2 mm, about 4 mm, about 5 mm, about 6 mm, about 7 mm, about8 mm, about 9 mm, about 10 mm, about 12 mm, about 14 mm, about 16 mm,about 18 mm, about 20 mm, about 25 mm, about 30 mm. Preferred surfaceareas of electrodes 20, 21, 22 and 23 range between about 1.0 sq. mm andabout 100 sq. mm, between about 2.0 sq. mm and about 50 sq. mm, andabout 4.0 sq. mm and about 25 sq. mm. Preferred lengths of electrodes20, 21, 22 and 23 range between about 0.25 mm and about 10 mm, betweenabout 0.50 mm and about 8 mm, and about 1.0 mm and about 6 mm.Electrodes 20, 21, 22 and 23 are preferably formed of platinum, althoughother metals and metal alloys may be employed such as stainless steel orgold.

[0082] The distal portion of lead 16 extends to a target site orposition near a desired nerve or nerve portion 8, and is preferably heldin such position by lead anchor 19. Note that lead anchor 19 may assumeany of a number of different structural configurations such one or moresuture sleeves, tines, barbs, hooks, a helical screw, tissue in-growthmechanisms, adhesive or glue.

[0083] One, two, three, four or more electrodes 20, 21, 22 and 23 may bedisposed at the distal end of lead 16 and/or lead 18. Electrodes 20, 21,22 and 23 are preferably arranged in an axial array, although othertypes of arrays may be employed such as inter-lead arrays of electrodesbetween the distal ends of leads 16 and 18 such that nerves or nerveportions 8 disposed between leads 16 and 18 may be stimulated. Electrodeconfigurations, arrays and stimulation patterns and methods similar tothose disclosed by Holsheimer in U.S. Pat. No. 6,421,566 entitled“Selective Dorsal Column Stimulation in SCS, Using Conditioning Pulses,”U.S. Pat. No. 5,643,330 entitled “Multichannel Apparatus for EpiduralSpinal Cord Stimulation” and U.S. Pat. No. 5,501,703 entitled“Multichannel Apparatus for Epidural Spinal Cord INS,” the respectiveentireties of which are hereby incorporated by reference herein, mayalso be adapted or modified for use in the present invention. Electrodeconfigurations, arrays, leads, stimulation patterns and methods similarto those disclosed by Thompson in U.S. Pat. No. 5,800,465 entitled“System and Method for Multisite Steering of Cardiac Stimuli,” theentirety of which is hereby incorporated by reference herein, may alsobe adapted or modified for use in the present invention to permit thesteering of electrical fields. Thus, although the Figures show certainelectrode configurations, other lead locations and electrodeconfigurations are possible and contemplated in the present invention.

[0084] Leads 16 and 18 preferably range between about 4 inches and about20 inches in length, and more particularly may be about 6 inches, about8 inches, about 10 inches, about 12 inches, about 14 inches, about 16inches or about 18 inches in length, depending on the location of thesite to be stimulated and the distance of INS 10 from such site. Otherlead lengths such as less than about 4 inches and more than about 20inches are also contemplated in the present invention.

[0085] Typically, leads 16 and 18 are tunneled subcutaneously betweenthe location of INS 10 and the location or site of the nerve or nerveportion that is to be stimulated. INS 10 is typically implanted in asubcutaneous pocket formed beneath the patient's skin according tomethods well known in the art. Further details concerning variousmethods of implanting INS 10 and leads 16 and 18 are disclosed in theMedtronic Interstim Therapy Reference Guide published in 1999, theentirety of which is hereby incorporated by reference herein. Othermethods of implanting and locating leads 16 and 18 are also contemplatedin the present invention.

[0086] U.S. patent application Ser. No. 10/004,732 entitled “ImplantableMedical Electrical Stimulation Lead Fixation Method and Apparatus” andSer. No. 09/713,598 entitled “Minimally Invasive Apparatus forImplanting a Sacral Stimulation Lead” to Mamo et al., the respectiveentireties of which are hereby incorporated by reference herein,describe methods of percutaneously introducing leads 16 and 18 to adesired nerve stimulation site in a patient.

[0087] Some representative examples of leads 16 and 18 include MEDTRONICnerve stimulation lead model numbers 3080, 3086, 3092, 3487, 3966 and4350 as described in the MEDTRONIC Instruction for Use Manuals thereof,all hereby incorporated by reference herein, each in its respectiveentirety. Some representative examples of INS 10 include MEDTRONICimplantable electrical INS model numbers 3023, 7424, 7425 and 7427 asdescribed in the Instruction for Use Manuals thereof, all herebyincorporated by reference herein, each in its respective entirety. Seealso FIGS. 4b through 4 f hereof, which disclose various embodiments ofleads 16 and 18 suitable for use in accordance with the presentinvention. INS 10 may also be constructed or operate in accordance withat least some portions of the implantable INSs disclosed in U.S. Pat.No. 5,199,428 to Obel et al., U.S. Pat. No. 5,207,218 to Carpentier etal. or U.S. Pat. No. 5,330,507 to Schwartz, all of which are herebyincorporated by reference herein, each in its respective entirety.

[0088] Lead locations and electrode configurations other than thoseexplicitly shown and described here are of course possible andcontemplated in the present invention. Lead anchors 19 are shown in FIG.4c as a series of tines.

[0089]FIG. 1 shows the general environment of a gastro-electricstimulation system of the present invention. The patient depiction showsan abdomen, a digestive system, a stomach, a duodenum, an intestine, apancreas, an enteric nervous system, and a vagus nerve. Thegastro-electric stimulation system may be implanted, or may be locatedoutside the patient. A programmer, separate from the gastro-electricstimulation system, may be used to modify parameters of thegastro-electric stimulation system. Programming may be accomplished witha console remote programmer such as a Model 7432 and Model 7457 memorymodule software or with a hand-held programmer such as an Itrel EZ,available from Medtronic, Inc. of Minneapolis, Minn.

[0090]FIG. 2a shows a block diagram of one embodiment of an open-loopgastro-electric stimulation system of the present invention. FIG. 2bshows a block diagram of a closed-loop gastro-electric stimulationsystem. FIG. 2c shows a block diagram of yet another embodiment of aclosed loop gastro-electric stimulation system of the present inventionhaving a wireless connection between physiologic sensor 30 and INS 10.

[0091] In a closed-loop embodiment of the present invention, the systemis preferably configured such that INS 10 is temporarily disabled so asnot to provide electrical stimulation signals to nerve site or portion 8after sensor 30 has detected, for example, an increase in gastric acidpH values above an accepted normal pH value. See, for example, U.S. Pat.No. 6,097,984 to Douglas, hereby incorporated by reference herein, inits entirety. Physiologic sensor 30 may be any of a number of suitablesensor types, such as a pH sensor, or any other sensor capable ofsensing changes in gastric acidity or changes in the frequency ofgastric acid production such as chemical or molecular sensors. Forexample, the sensed parameter may be pH, sensed either in the esophagusor in the stomach, may be an agonist for gastric acid secretion (e.g.,acetylcholine, histamine, gastrin), or may be an antagonist for gastricacid secretion (e.g., prostaglandin, somatostatin, EGF, proglumide).

[0092]FIG. 2d shows an illustrative signal amplitude vs. time chartobtained in accordance with the present invention in respect ofphysiologic sensor 30 and the output signal generated thereby as afunction of time. In such a closed-loop feedback control embodiment ofthe present invention, sensor 30 and sensing and computing circuitry inINS 10 cooperate to detect when a sensed signal has fallen below orrisen above a predetermined threshold, as the case may be. Once thesensed signal has remained above or below the predetermined thresholdfor a predetermined period of time, stimulating circuitry in INS 10 isdisabled. Such stimulating circuitry in INS 10 is subsequently enabledor activated when the sensed signal has once again risen above or fallenbelow the same or a different predetermined threshold.

[0093] Some examples of sensor technology that may be adapted for use insome embodiments of the present invention include those disclosed in thefollowing U.S. patents: U.S. Pat. No. 5,640,764 for “Method of forming atubular feed-through hermetic seal for an implantable medical device;”U.S. Pat. No. 5,660,163 for “Glucose sensor assembly;” U.S. Pat. No.5,750,926 for “Hermetically sealed electrical feedthrough for use withimplantable electronic devices;” U.S. Pat. No. 5,791,344 for “Patientmonitoring system;” U.S. Pat. No. 5,917,346 for “Low power current tofrequency converter circuit for use in implantable sensors;” U.S. Pat.No. 5,957,958 for “Implantable electrode arrays;” U.S. Pat. No.5,999,848 for “Daisy chainable sensors and stimulators for implantationin living tissue;” U.S. Pat. No. 6,043,437 for “Alumina insulation forcoating implantable components and other microminiature devices;” U.S.Pat. No. 6,088,608 for “Electrochemical sensor and integrity teststherefor;” U.S. Pat. No. 6,259,937 for “Implantable substrate sensor.”

[0094] Each of the foregoing patents is incorporated by referenceherein, each in its respective entirety.

[0095] In another embodiment of the present invention, an overalltherapy aimed at decreasing gastric acid production and/or increasinggastric acid pH may best be delivered by applying a gastric acidsecretion “increase signal” for a period of time after a meal has beeningested by a patient. Feedback control algorithms and methods of thepresent invention may also employ sensing or determining one or more ofa patient's rate of gastric acid secretion or production, duodenumsalinity, gastric acid impedance, gastric acid electrical activity,motion, pain, weight, nausea, and/or vomiting. As outlined above, suchpatient conditions may be sensed, measured or determined using anappropriate sensor or sensors that generates a corresponding outputsignal which is routed to the input of INS 10 for use in controllingelectrical stimulation signals. The patient's condition may also bemeasured by the patient or a physician, who then employs the measuredcondition to control the electrical stimulation signal output providedby INS 10.

[0096]FIG. 3 shows a block diagram illustrating some of the constituentcomponents of INS 10 in accordance with one embodiment of the presentinvention, where INS 10 has a microprocessor-based architecture. Otherarchitectures of INS 10 are of course contemplated in the presentinvention, such as the logic or state machine architecture employed inthe Medtronic Model Number 3023 INS. For the sake of convenience, INS 10in FIG. 3 is shown with only one lead 16 connected thereto; similarcircuitry and connections not shown in FIG. 2 apply generally to lead 18and other additional leads not shown in the drawings. INS 10 in FIG. 3is most preferably programmable by means of external programming unit 11shown in FIG. 1b. One such programmer is the commercially availableMedtronic Model No. 7432 programmer, which is microprocessor-based andprovides a series of encoded signals to INS 10, typically through aprogramming head which transmits or telemeters radio-frequency (RF)encoded signals to INS 10. Another suitable programmer is thecommercially available Medtronic Model No. 8840 programmer, which isalso microprocessor-based but features a touch control screen. Any of anumber of suitable programming and telemetry methodologies known in theart may be employed so long as the desired information is transmitted toand from the implantable electrical INS 10.

[0097] As shown in FIG. 3, INS 10 receives input signals via physiologicsensor 30 and delivers output stimulation signals to lead 16. INS 10most preferably comprises a CPU, processor, controller ormicro-processor 31, power source 32 (most preferably a primary orsecondary battery), clock 33, memory 34, telemetry circuitry 35, input36 and output 37. Electrical components shown in FIG. 3 may be poweredby an appropriate implantable primary (i.e., non-rechargeable) batterypower source 32 or secondary (i.e., rechargeable) battery power source32. INS 10 may also contain a battery or capacitor which receives powerfrom outside the body by inductive coupling between an externaltransmitter and an implanted receiver. For the sake of clarity, thecoupling of power source 32 to the various components of INS 10 is notshown in the Figures. An antenna is connected to processor 31 via adigital controller/timer circuit and data communication bus to permituplink/downlink telemetry through RF transmitter and receiver telemetryunit 35. By way of example, telemetry unit 35 may correspond to thatdisclosed in U.S. Pat. No. 4,566,063 issued to Thompson et al. It isgenerally preferred that the particular programming and telemetry schemeselected permit the entry and storage of electrical stimulationparameters. The specific embodiments of the antenna and other telemetrycircuitry presented herein are shown for illustrative purposes only, andare not intended to limit the scope of the present invention.

[0098] An output pulse generator provides pacing stimuli to the desirednerve or nerve portion through, for example, a coupling capacitor inresponse to a trigger signal provided by a digital controller/timercircuit, when an externally transmitted stimulation command is received,or when a response to other stored commands is received. By way ofexample, an output amplifier of the present invention may correspondgenerally to an output amplifier disclosed in U.S. Pat. No. 4,476,868 toThompson, hereby incorporated by reference herein in its entirety. Thespecific embodiments of such an output amplifier are presented forillustrative purposes only, and are not intended to be limiting inrespect of the scope of the present invention. The specific embodimentsof such circuits may not be critical to practicing some embodiments ofthe present invention so long as they provide means for generating anappropriate train of stimulating pulses to the desired nerve or nerveportion.

[0099] In various embodiments of the present invention, INS 10 may beprogrammably configured to operate so that it varies the rate at whichit delivers stimulating pulses to the desired nerve or nerve portion 8in response to one or more selected outputs being generated. INS 10 mayfurther be programmably configured to operate so that it may vary themorphology of the stimulating pulses it delivers. Numerous implantableelectrical INS features and functions not explicitly mentioned hereinmay be incorporated into INS 10 while remaining within the scope of thepresent invention. Various embodiments of the present invention may bepracticed in conjunction with one, two, three or more leads, or inconjunction with one, two, three, four or more electrodes.

[0100] It is important to note that leadless embodiments of the presentinvention are also contemplated, where one or more stimulation and/orsensing electrode capsules or modules are implanted at or near a desirednerve stimulation site, and the capsules or modules deliver electricalstimuli directly to the site using a preprogrammed stimulation regime,and/or the capsules or modules sense electrical or other pertinentsignals. Such capsules or modules are preferably powered by rechargeablebatteries that may be recharged by an external battery charger usingwell-known inductive coil or antenna recharging means, and preferablycontain electronic circuitry sufficient to permit telemetriccommunication with a programmer, to deliver electrical stimuli and/orsense electrical or other signals, and to store and execute instructionsor data received from the programmer. Examples of methods and devicesthat may be adapted for use in the wireless devices and methods of thepresent invention include those described in U.S. Pat. No. 6,208,894 toSchulman et al. entitled “System of implantable devices for monitoringand/or affecting body parameters;” U.S. Pat. No. 5,876,425 to Schulmanet al. entitled “Power control loop for implantable tissue stimulator;”U.S. Pat. No. 5,957,958 to Schulman et al. entitled “Implantableelectrode arrays;” and U.S. patent application Ser. No. 09/030,106 filedFeb. 25, 1998 to Schulman et al. entitled “Battery-Powered PatientImplantable Device,” all of which are hereby incorporated by referenceherein, each in its respective entirety.

[0101]FIG. 4a illustrates one embodiment of an implantablegastro-electric stimulation system suitable for use in the presentinvention, where the system comprises INS 10 and at least one associatedmedical electrical lead 16. INS 10 may be an implantable pulse generator(INS) such as a MEDTRONIC ITREL® 3 Model 7425 implantable INS, thatproduces or generates an electrical stimulation signals adapted for thepurposes of the present invention. INS 10 may be surgically implantedsuch as in a subcutaneous pocket in the abdomen or positioned outsidethe patient. When positioned outside the patient, the INS 10 may beattached to the patient. INS 10 may be programmed to modify parametersof the delivered electrical stimulation signal such as frequency,amplitude, and pulse width in accordance with various embodiments of thepresent invention. By way of example, one or more leads 16 and 18 may beimplanted into the muscle wall of the stomach such that lead electrodes20 through 24 of adjacent leads are between about 0.5 cm apart to about10.0 cm apart, and may be located proximal to the plexus where the vagusnerve joins the stomach.

[0102]FIGS. 4b through 4 f show various embodiments of the distal end oflead 16 of the present invention. In FIGS. 4b and 4 e, lead 16 is apaddle lead where electrodes 20-23 are arranged along an outwardlyfacing planar surface. Such a paddle lead is preferably employed tostimulate peripheral nerves. In FIG. 4c, lead 16 is a conventionalquadrapolar lead having no pre-attached anchoring mechanism whereelectrodes 20-23 are cylindrical in shape and extend around thecircumference of the lead body. In FIG. 4d, lead 16 is a quadrapolarlead having tined lead anchors. The tines may be formed from flexible orrigid biocompatible materials in accordance with the application athand. Representative examples of some tined and other types of leadssuitable, adaptable or modifiable for use in conjunction with thesystems, methods and devices of the present invention include thosedisclosed in U.S. patent application Ser. No. 10/004,732 entitled“Implantable Medical Electrical Stimulation Lead Fixation Method andApparatus” and Ser. No 09/713,598 entitled “Minimally Invasive Apparatusfor Implanting a Sacral Stimulation Lead” to Mamo et al., and thosedisclosed in U.S. Pat. No. 3,902,501 to Citron entitled “EndocardialLead,” U.S. Pat. No. 4,106,512 to Bisping entitled “TransvenouslyImplantable Lead,” and U.S. Pat. No. 5,300,107 to Stokes entitled“Universal Tined Myocardial Pacing Lead.” In FIG. 4d, lead 16 is aquadrapolar lead having a pre-attached suture anchor. In FIG. 4e, lead16 comprises needle anchor/electrode 19/20 disposed at its distal endand suture anchor 19.

[0103]FIG. 4f shows lead 16 as a tri-polar cuff electrode, wherecuff/anchor 19 is wrapped around desired nerve or nerve portion 8 tothereby secure the distal end of lead 16 to the nerve and positionelectrodes 20-22 against or near nerve or nerve portion 8. The MedtronicModel No. 3995 cuff electrode lead is one example of a lead that may beadapted for use in the present invention, the Instructions for Usemanual of which entitled “INTERSTIM Manual: Model 3995 Implantablebipolar peripheral nerve and spinal root stimulation lead” is herebyincorporated by reference herein in its entirety.

[0104]FIGS. 5a through 5 d illustrate representative cross-sectionalviews of gross and microscopic portions of a patient's stomach. Theproximal stomach is the fundus and the distal stomach is the body andantrum. The pyloric sphincter joins the antrum and the duodenum.Parasympathetic input to the stomach is supplied by the vagus nerve andthe sympathetic nervous system innervates the stomach through thesplanchnic nerves. On the greater curvature of the stomach between thefundus and the body is the general region of the pacemaker of thestomach. A telescoped and cross-sectional view of the antrum is shown inthe circle in the middle of FIG. 5a. This view shows the gastric wallwith the mucosal layer and the muscularis. The outermost muscle layer isthe longitudinal layer; and running perpendicular to the longitudinalmuscle layer is the circular muscle layer. There is also an obliquemuscle layer in the stomach. Between the circular muscle andlongitudinal muscle layers are neurons of the myenteric plexus and theenteric nervous system. The second telescoped view shown in the lowercircle illustrates the anatomic proximities of the myenteric neurons andthe interstitial cells of Cajal in the myenteric region between thecircular and longitudinal muscle layers. The processes of theinterstitial cells interdigitate with circular muscle fibers and themyenteric neurons. The interstitial cells in the myenteric plexus areaare thought to be responsible for generation of slow waves or pacesetterpotentials. The interstitial cells are also found in the submucosallayers, the deep musculatures plexus, and the intramuscular layers ofthe stomach. Leads 16 and 18 and electrodes 20-24 may be implanted in orin the vicinity of any one or more of the serosa layer, the myentericplexus, the submucosal plexus, or any of the various layers of themuscularis (i.e., the oblique, circular or longitudinal layers).

[0105] In accordance with several embodiments of the present invention,FIGS. 6a through 6 f illustrate various locations for the placement ofstimulation and sensing electrodes in and near the stomach. Electrodes20 through 24 are placed in electrical contact or in proximity to targetnerve or nerve portion 8. The electrode location is selected based uponthe obtained innervation of the vagus nerve and digestive system, theselected location's suitability for electrode connection, and the degreeto which the location proves efficacious for treating acid production orgastric acid pH in a particular patient. Locations most suitable forelectrode attachment and connection should be easily accessible bysurgical or endoscopic means, and further be sufficiently mechanicallyrobust and substantial to secure and retain electrodes 20-24 of leads 16and/or 18.

[0106] Some specific electrode locations that are well innervated, andsurgically or endoscopically accessible include, but are not limited to:(a) the plexus on the anterior superior and/or the anterior inferiorpancreaticoduodenal arteries; (b) the plexus on the inferiorpancreaticoduodenal artery; (c) the plexus on the jejunal artery; (d)the superior mesenteric artery and plexus; (d) the plexus on thegastroepiploic arteries; (e) the celiac ganglia and plexus; (f) thesplenic artery and plexus; (g) the left lesser thoracic splanchic nerve;(h) the left greater thoracic splanchic nerve; (i) the principalanterior gastric branch of the anterior vagal trunk; (j) the leftgastric artery and plexus; (k) the celiac branch of the anterior vagaltrunk; (I) the anterior vagal trunk; (m) proximal, distal or portionsbetween the proximal and distal portions of the vagus nerve; (n) thehepatic branch of the anterior vagal trunk; (O) the right and/or leftinferior phrenic arteries and plexus; (p) the anterior posterior layersof the lesser omenium; (q) the branch from the hepatic plexus to thecardia via the lesser omenium; (r) the right greater thoracic splanchicnerve; (s) the vagal branch from the hepatic plexus to the pylorus; (t)the right gastric artery and plexus. Note that as discussed above, it iscontemplated in the present invention that multiple leads be employed.

[0107]FIG. 7 illustrates some of the various locations in or near thestomach and/or vagus nerve of a patient for placing feedback controlsensors according to some embodiments of closed-loop feedback controlsystems of the present invention.

[0108]FIGS. 8a through 8 c illustrate various representative electricalstimulation pulse, regime and control parameters according to someembodiments of the present invention. FIG. 8a illustrates a typicalcharge balanced square pulse used in many implantable electricalstimulation systems. As shown, amplitude, pulse width, and pulse rateare adjustable. FIG. 8b shows a timing diagram illustrating the outputof INS 10 when the output signal provided thereby successively gated onand off. In FIG. 8b, INS 10 is set to a frequency of 14 pulses persecond, but is gated on for 0.1 seconds, and off for 5 seconds,resulting in an output of two pulses every five seconds. The on and offgating periods may be adjusted over a wide range.

[0109] In the present invention, electrical stimulation signalparameters may be selected to influence gastric acid secretion throughdirect stimulation of a nerve or nerve portion 8, by stimulatingafferent nerves or nerve portions 8, by stimulating efferent nerves ornerve portions 8, or by stimulating some combination of the foregoingnerves or nerve portions 8. The electrical stimulation signal ispreferably charge-balanced for biocompatibility, and adapted to decreasegastric acid production and/or increase pH. For example, a gastric acid“decrease signal” is adapted to decrease the quantity of gastric acidsecreted by the stomach lining, and accordingly has a frequency, phase,amplitude and morphology selected to signal the stomach to decrease theproduction of gastric acid. Such a “decrease signal” has a frequencyranging between about 0.10 pulses per minute and about 18,000 pulses perminute.

[0110] In the event multiple signals are employed to stimulate a desiredsite, the spatial and/or temporal phase between the signals may beadjusted or varied to produce the desired stimulation pattern orsequence. That is, in the present invention beam forming and specificsite targeting via electrode array adjustments are contemplated.Examples of lead and electrode arrays and configurations that may beadapted for use in some embodiments of the present invention so as tobetter steer, control or target electrical stimulation signals providedthereby in respect of space and/or time include those disclosed in U.S.Pat. No. 5,501,703 to Holsheimer; U.S. Pat. No. 5,643,330 to Holsheimer;U.S. Pat. No. 5,800,465 to Thompson; U.S. Pat. No. 6,421,566 toHolsheimer; and U.S. Patent Application Publication No. 20020128694A1 toHolsheimer.

[0111] Representative ranges of preferred electrical pulse stimulationparameters capable of being delivered by INS 10 through leads 16 and 18include the following: Frequency: Between about 50 Hz and about 100 Hz ;Between about 10 Hz and about 250 Hz; and Between about 0.5 Hz and about500 Hz. Amplitude: Between about 1 Volt and about 10 Volts; Betweenabout 0.5 Volts and about 20 Volts; and Between about 0.1 Volts andabout 50 Volts. Pulse Width: Between about 180 microseconds and about450 microseconds; Between about 100 microseconds and about 1000microseconds; Between about 10 microseconds and about 5000 microseconds.

[0112] Further exemplary stimulation parameters of the system of thepresent invention include:

[0113] (a) A stimulation signal frequency ranging between:

[0114] (i) about 0.10 to about 18,000 pulses per minute;

[0115] (ii) about 1 to about 5,000 pulses per minute;

[0116] (iii) about 1 to about 1,000 pulses per minute;

[0117] (iv) about 1 to about 100 pulses per minute;

[0118] (v) about 3 to about 25 pulses per minute;

[0119] (b) A stimulation signal pulse width ranging between:

[0120] (i) about 0.01 mS to about 500 mS;

[0121] (ii) about 0.1 mS to about 100 mS;

[0122] (iii) about 0.1 mS to about 10 mS;

[0123] (iv) about 0.1 mS to about 1 mS;

[0124] (c) A stimulation signal current ranging between:

[0125] (i) about 0.01 mA to about 500 mA;

[0126] (ii) about 0.1 mA to about 100 mA;

[0127] (iii) about 0.1 mA to about 10 mA;

[0128] (iv) about 1 mA to 100 mA, and

[0129] (v) about 1 to about 10 mA.

[0130] (d) A stimulation signal which occurs continuously in accordancewith the parameters of (a), (b), and (c) above, or a combinationthereof;

[0131] (e) A stimulation signal which occurs discontinuously when thesystem turns on and off, where on and off are defined as a cycle timewhich may vary between about 1 second and about 60 seconds (for example,on=0.1 seconds, and off=5 seconds; on=1.0 sec and off=4 seconds, and soon; see FIGS. 8b and 8 c).

[0132] (f) Stimulation signals having morphologies best characterized as(i) spikes, (ii) sinusoidal waves, or (iii) square pulses;

[0133]FIG. 9 illustrates several methods of stimulating a patient'sstomach and/or vagus nerve so as to lower the amount of gastric acidsecretions and/or to lower the acidity of such secretions in a patient.In FIG. 9, step 110 is employed to determine one or more desired nervestimulation locations (as illustrated in FIG. 5a through 5 d and FIGS.6a through 6 f) positioned near or at one or more of the nerves 8, nerveportions 8, or locations near a nerve or nerve portion 8. Step 130 isemployed to implant INS 10 in an appropriate location within the patientsuch that the proximal end of lead 16 may be operably connected theretoand such that INS 10 is placed in such a location that discomfort andthe risk of infection to the patient are minimized. Next INS 10 isoperably connected to lead 16, which may or may not require the use ofoptional lead extension 15 and lead connector 13. In Step 150, INS 10 isactivated and stimulation pulses are delivered to electrodes 20, 21, . .. n through lead 16 to the desired nerve stimulation location. In step160, the electrical pulse stimulation parameters are adjusted tooptimize the therapy delivered to the patient. Such adjustment mayentail one or more of adjusting the number or configuration ofelectrodes or leads used to stimulate the selected location, pulseamplitude, pulse frequency, pulse width, pulse morphology (e.g., squarewave, triangle wave, sinusoid, biphasic pulse, tri-phasic pulse, etc.),times of day or night when pulses are delivered, pulse cycling times,the positioning of the lead or leads, and/or the enablement ordisablement of “soft start” or ramp functions respecting the stimulationregime to be provided. In step 170 the operating mode of the implantedsystem is selected. Optionally, parameters selected in step 160 may beadjusted after the operating mode has been selected to optimize therapy.

[0134]FIG. 10 shows test data obtained in accordance with one embodimentof the present invention. Canines were instrumented acutely with fourelectrodes arranged circumferentially around the vagal neural plexus onthe stomach. These leads were hooked up to an INS. The dog's stomachswere cannulated and clamped below the pylorus. Data collection occurredevery 15 minutes. At the start of a 15-minute interval, 240 mL of warmsaline was introduced into the stomach via the cannula. At the end ofthe interval, the saline was removed via suction and measured for volumeand pH. During the course of the experiment, the dogs were infusedcontinuously with pentagastrin to stimulate acid secretion. Variousstimulation patterns-interspersed with rest periods were tried tomodulate acid production.

[0135] The graph of pH versus time from the above-described animalexperiment is shown in FIG. 10. These data suggest that vagalstimulation did have some effect on gastric acid secretions. Whenstimulation was applied, the pH rose and then fell when the INS wasturned off.

[0136] In addition, in the present invention it is contemplated thatdrugs be delivered to specific sites within a patient using well knownfully implantable drug pump devices in combination with providingelectrical stimulation to the nerves or nerve portions described above.According to such a method, the drug pump may be incorporated into thesame housing as INS 10, or be separate therefrom in its own hermeticallysealed housing. The drug catheter attached to the implantable drug pumpthrough which the drug is delivered to the specific site may also beincorporated into lead 16 or 18, or may be separate therefrom. Drugs ortherapeutic agents delivered in accordance with this method include, butare not limited to, antibiotics, pain relief agents such as demerol andmorphine, radioactive or radiotherapeutic substances or agents forkilling or neutralizing cancer cells, genetic growth factors forencouraging the growth of healthy tissues, and the like.

[0137] Also hereby incorporated by reference herein in its entirety isU.S. Patent Application Number 20020082665A1 to Haller et al. publishedJun. 27, 2002 and entitled “System and Method of Communicating betweenan Implantable Medical Device and a Remote Computer System or HealthCare Provider.” In the present invention it is further contemplated thatthe methods and devices described hereinabove be extended to include thecommunication system of Hailer et al. for at least one of monitoring theperformance of INS 10 and/or an implantable drug pump implanted withinthe body of a patient, monitoring the health of the patient and remotelydelivering an electrical stimulation and/or drug therapy to the patientthrough INS 10 and/or the optional implantable drug pump, INS 10 or theimplantable drug pump being capable of bi-directional communication witha communication module located external to the patient's body, thesystem comprising: (a) INS 10 and optionally the implantable drug pump;(b) the communication module; (c) a mobile telephone or similar deviceoperably connected to the communication module and capable of receivinginformation therefrom or relaying information thereto; (e) a remotecomputer system, and (f) a communication system capable of bidirectionalcommunication.

[0138] According to further embodiments of the present invention, aningestible or implantable pill-shaped or capsular device is employedwhich is capable of sensing one or more physical parameters such as pH,hormonal levels and the like, and recording, storing or transmitting toan external receiver by, for example, RF means, information regardingthe parameter(s) sensed by the device acidity. The sensed parameterinformation may then be employed to control or refine thegastro-electric stimulation parameters. Examples of devices that may beso adapted in accordance with some embodiments of the present inventioninclude: U.S. Pat. No. 4,844,076 for “Ingestible Size ContinuouslyTransmitting Temperature Monitoring Pill” to Lesho et al.; U.S. Pat. No.5,170,801 for “Medical Capsule Device Actuated by Radio-Frequency (RF)Signal” to Casper et al.; U.S. Pat. No. 5,279,607 for “Telemetry Capsuleand Process” to Schentag et al.; U.S. Pat. No. 5,395,366 for “SamplingCapsule and Process” to D'Andrea et al.; U.S. Pat. No. 6,285,897 for“Remote Physiological Monitoring System” to Kilcoyne et al.; U.S. Pat.No. 6,428,469 for “Energy Management of a Video Capsule” to Iddan etal.; U.S. Patent Application Publication No. 20020055734 for “IngestibleDevice” to Houzego et al.; U.S. Patent Application Publication No.20020132226 for “Ingestible Electronic Capsule” to Nair et al.; and U.S.Patent Application Publication No. 20020198470 for “Capsule and Methodfor Treating or Diagnosing the Intestinal Tract” to Imran et al..

[0139] According to other embodiments of the present invention,implantable sensors and/or stimulation modules or leads may be implantedin desired portions of the gastro-intestinal tract by means of avacuum-operated device which is endoscopically or otherwise emplacedwithin the gastrointestinal tract, followed by a portion of the tractbeing sucked up into a receiving chamber of the device, and the sensor,module or lead being implanted within the tissue held within thereceiving chamber. See, for example, U.S. Pat. No. 6,098,629 for“Submucosal Esophageal Bulking Device” to Johnson et al.; U.S. Pat. No.6,338,345 for “Submucosal Prosthesis Delivery Device” to Johnson et al.;U.S. Pat. No. 6,401,718 for “Submucosal Prosthesis Delivery Device” toJohnson et al.; and PCT Patent Application WO 02087657 for “GastricDevice and Suction Assisted Method for Implanting a Device on a StomachWall” assigned to Intrapace, Inc.

[0140] In still further embodiments of the present invention, variouscomponents of the gastrointestinal electrical stimulation system may beextended, miniaturized, rendered wireless, powered, recharged ormodularized into separate or discrete components in accordance with theteachings of, by way of example: U.S. Pat. No. 5,193,539 for“Implantable Microstimulator” to Schulman et al.; U.S. Pat. No.5,193,540 for “Structure and Method of Manufacture of an ImplantableMicrostimulator” to Schulman et al.; U.S. Pat. No. 5,324,316 for“Implantable Microstimulators” to Schulman et al.; U.S. Pat. No.5,358,514 for “Implantable Microdevice With Self-Attaching Electrodes”to Schulman et al.; U.S. Pat. No. 5,405,367 for “Structure and Method ofManufacture of an Implantable Microstimulator” to Schulman et al.; U.S.Pat. No. 5,957,958 for “Implantable Electrode Arrays” to Schulman etal.; U.S. Pat. No. 5,999,848 for “Daisy Chainable Sensors andStimulators for Implantation in Living Tissue” to Gord et al.; U.S. Pat.No. 6,051,017 for “Implantable Microstimulator and Systems Employing theSame” to Loeb et al.; U.S. Pat. No. 6,067,474 for “Implantable DeviceWith Improved Battery Recharging and Powering Configuration” to Schulmanet al.; U.S. Pat. No. 6,205,361 for “Implantable Expandable MulticontactElectrodes” to Kuzma et al.; U.S. Pat. No. 6,212,431 for “Power TransferCircuit for Implanted Devices” to Hahn et al.; U.S. Pat. No. 6,214,032for “System for Implanting a Microstimulator” to Loeb; U.S. Pat. No.6,315,721 for “System of Implantable Devices for Monitoring and/orAffecting Body Parameters” to Schulman et al.; U.S. Pat. No. 6,393,325for “Directional Programming for Implantable Electrode Arrays” to Mannet al.; U.S. Pat. No. 6,516,227 for “Rechargeable Spinal Cord StimulatorSystem” to Meadows et al.

[0141] The preceding specific embodiments are illustrative of thepractice of the invention. It is to be understood, therefore, that otherexpedients known to those skilled in the art or disclosed herein may beemployed without departing from the invention or the scope of theappended claims. For example, the present invention is not limited tothe use of any particular specific configuration of an INS, leads orelectrodes shown explicitly in the drawings hereof. Those skilled in theart will understand immediately that many variations and permutations ofknown implantable devices may be employed successfully in the presentinvention.

[0142] In the claims, means plus function clauses are intended to coverthe structures described herein as performing the recited function andtheir equivalents. Means plus function clauses in the claims are notintended to be limited to structural equivalents only, but are alsointended to include structures which function equivalently in theenvironment of the claimed combination. All printed publications andpatents referenced hereinabove are hereby incorporated by referencedherein, each in its respective entirety.

We claim:
 1. A gastro-electric stimulation system for at least one ofreducing the pH of gastric acid in a stomach of a patient and reducingan amount of gastric acid produced in the stomach of the patient,comprising: a INS for producing at least one electrical stimulationsignal; at least one medical electrical lead having a proximal end and adistal end, the proximal end being connected to the INS, the distal endbeing adapted for positioning the lead in a lead position comprising atleast one of near the patient's stomach, near a selected nerve and neara nerve portion; and, at least two electrodes disposed near the medicalelectrical lead distal end, the electrodes being electrically connectedthrough the medical electrical lead to the INS to receive the at leastone electrical stimulation signal and convey such signal to theelectrode position; wherein the electrical stimulation signal isprovided in an amount and manner effective to at least of reduce the pHof the gastric acid in the patient and reduce the amount of gastric acidproduced in the stomach of a patient.
 2. The gastro-electric stimulationsystem of claim 1, wherein the electrode position is selected from thegroup consisting of the stomach, the vagus nerve, the plexus on theanterior superior and/or the anterior inferior pancreaticoduodenalarteries, the plexus on the inferior pancreaticoduodenal artery, theplexus on the jejunal artery, the superior mesenteric artery and plexus,the plexus on the gastroepiploic arteries, the celiac ganglia andplexus, the splenic artery and plexus, the left lesser thoracicsplanchic nerve, the left greater thoracic splanchic nerve, theprincipal anterior gastric branch of the anterior vagal trunk, the leftgastric artery and plexus, the celiac branch of the anterior vagaltrunk, the anterior vagal trunk, proximal, distal or portions betweenthe proximal and distal portions of the vagus nerve, the hepatic branchof the anterior vagal trunk, the right and/or left inferior phrenicarteries and plexus, the anterior posterior layers of the lesseromenium, the branch from the hepatic plexus to the cardia via the lesseromenium, the right greater thoracic splanchic nerve, the vagal branchfrom the hepatic plexus to the pylorus, the right gastric artery, theplexus and the intestine, and branches or portions thereof.
 3. Thegastro-electric stimulation system of claim 1, wherein the electricalstimulation signal frequency ranges between about 0.1 pulses per minuteand about 18,000 pulses per minute.
 4. The gastro-electric stimulationsystem of claim 1, wherein the electrical stimulation signal pulse widthranges between about 0.01 mS and about 500 mS.
 5. The gastro-electricstimulation system of claim 1, wherein the electrical stimulation signalhas a peak amplitude ranging between about 0.01 mA and about 100.0 mA.6. The gastro-electric stimulation system of claim 1, wherein theelectrical stimulation signal is provided in an amount and mannersufficient to influence at least one of the stomach, the vagus nerve,the plexus on the anterior superior and/or the anterior inferiorpancreaticoduodenal arteries, the plexus on the inferiorpancreaticoduodenal artery, the plexus on the jejunal artery, thesuperior mesenteric artery and plexus, the plexus on the gastroepiploicarteries, the celiac ganglia and plexus, the splenic artery and plexus,the left lesser thoracic splanchic nerve, the left greater thoracicsplanchic nerve, the principal anterior gastric branch of the anteriorvagal trunk, the left gastric artery and plexus, the celiac branch ofthe anterior vagal trunk, the anterior vagal trunk, proximal, distal orportions between the proximal and distal portions of the vagus nerve,the hepatic branch of the anterior vagal trunk, the right and/or leftinferior phrenic arteries and plexus, the anterior posterior layers ofthe lesser omenium, the branch from the hepatic plexus to the cardia viathe lesser omenium, the right greater thoracic splanchic nerve, thevagal branch from the hepatic plexus to the pylorus, the right gastricartery, the plexus and the intestine.
 7. The gastro-electric stimulationsystem of claim 1, wherein the electrical stimulation signal is adaptedto substantially influence efferent nerves.
 8. The gastro-electricstimulation system of claim 1, wherein the electrical stimulation signalis adapted to substantially influence afferent nerves.
 9. Thegastro-electric stimulation system of claim 1, further comprising asensor electrically connected to the INS, the sensor generating a sensorsignal indicative of a patient condition wherein the INS receives thesensor signal and controls the delivered electrical stimulation signalin response to the sensor signal.
 10. A system for at least one ofreducing the pH of gastric acid in a stomach of a patient and reducingan amount of gastric acid produced in the stomach of the patient,comprising: a pulse generator for generating stimulus pulses; and amedical electrical lead adapted to deliver the stimulus pulses to aportion of a patient's body; wherein the stimulus pulses and medicalelectrical lead cooperate to provide electrical stimulation, to aselected stimulation site in the patient, in an amount and mannereffective to at least one of reduce the pH of the gastric acid in thepatient and reduce the amount of gastric acid produced in the stomach ofthe patient.
 11. The system of claim 10, wherein the pulse generator isan implantable neurological stimulator.
 12. A gastro-electric stimulatorfor at least one of reducing the pH of gastric acid in a stomach of apatient and reducing an amount of gastric acid produced in the stomachof the patient, comprising: a neuro-electrical stimulator for producinga stimulation signal; at least one electrical lead having a proximal endand a distal end, the proximal end being connected to theneuro-electrical stimulator, the distal end being positionable in aselected lead position comprising at least one of near the patient'sstomach, near a selected nerve and near a nerve portion; and, at leasttwo electrodes disposed near the distal end of the electrical lead, theelectrodes being electrically connected through the electrical lead tothe neuro-electrical stimulator to receive the stimulation signal andconvey such signal to the selected electrode position
 13. Thegastro-electric stimulator of claim 12, wherein the electrode positionis selected from the group consisting of the stomach, the vagus nerve,the plexus on the anterior superior and/or the anterior inferiorpancreaticoduodenal arteries, the plexus on the inferiorpancreaticoduodenal artery, the plexus on the jejunal artery, thesuperior mesenteric artery and plexus, the plexus on the gastroepiploicarteries, the celiac ganglia and plexus, the splenic artery and plexus,the left lesser thoracic splanchic nerve, the left greater thoracicsplanchic nerve, the principal anterior gastric branch of the anteriorvagal trunk, the left gastric artery and plexus, the celiac branch ofthe anterior vagal trunk, the anterior vagal trunk, proximal, distal orportions between the proximal and distal portions of the vagus nerve,the hepatic branch of the anterior vagal trunk, the right and/or leftinferior phrenic arteries and plexus, the anterior posterior layers ofthe lesser omenium, the branch from the hepatic plexus to the cardia viathe lesser omenium, the right greater thoracic splanchic nerve, thevagal branch from the hepatic plexus to the pylorus, the right gastricartery, the plexus and the intestine, and branches or portions thereof.14. The gastro-electric stimulator of any of claims 12 and 13, whereinthe stimulation signal frequency ranges between about 0.10 pulses perminute and about 18,000 pulses per minute.
 15. The gastro-electricstimulator of any of claims 12 and 13, wherein the stimulation signalpulse width ranges between about 0.01 mS and about 500 mS.
 16. Thegastro-electric stimulator of any of claims 12 and 13, wherein thestimulation signal has a peak amplitude ranging between about 0.01 mAand about 500.0 mA.
 17. A method for at least one of reducing the pH ofgastric acid in a stomach of a patient and reducing an amount of gastricacid produced in the patient's stomach, comprising: diagnosing gastricacid in a patient's stomach comprising at least one of having anexcessive pH and being produced in excessive quantities; generatingelectrical stimulus pulses; and delivering the stimulus pulses to atleast one electrode stimulation site within the patient in an amount andmanner effective to at least one of reduce the pH of the gastric acidthe patient's stomach and reduce the amount of gastric acid produced inpatient's stomach.
 18. The method of claim 17, wherein the step ofdelivering stimulus pulses further comprises providing at least twoelectrodes across the at least one electrode stimulation site.
 19. Themethod of claim 18, wherein the step of providing at least twoelectrodes across the at least one electrode stimulation site furthercomprises selecting at least one of a selected portion of the patient'sstomach, a nerve and a nerve portion as the electrode stimulation site.20. The method of claim 18, wherein the step of providing at least twoelectrodes across the at least one electrode stimulation site furthercomprises selecting at least one of the stomach, the vagus nerve, theplexus on the anterior superior and/or the anterior inferiorpancreaticoduodenal arteries, the plexus on the inferiorpancreaticoduodenal artery, the plexus on the jejunal artery, thesuperior mesenteric artery and plexus, the plexus on the gastroepiploicarteries, the celiac ganglia and plexus, the splenic artery and plexus,the left lesser thoracic splanchic nerve, the left greater thoracicsplanchic nerve, the principal anterior gastric branch of the anteriorvagal trunk, the left gastric artery and plexus, the celiac branch ofthe anterior vagal trunk, the anterior vagal trunk, proximal, distal orportions between the proximal and distal portions of the vagus nerve,the hepatic branch of the anterior vagal trunk, the right and/or leftinferior phrenic arteries and plexus, the anterior posterior layers ofthe lesser omenium, the branch from the hepatic plexus to the cardia viathe lesser omenium, the right greater thoracic splanchic nerve, thevagal branch from the hepatic plexus to the pylorus, the right gastricartery, the plexus and the intestine as the electrode stimulation site.21. The method of any of claims 17-20, wherein the stimulation signalfrequency ranges between about 0.10 pulses per minute and about 18,000pulses per minute.
 22. The method of any of claims 17-20, wherein thestimulation signal pulse width ranges between about 0.01 mS and about500 mS.
 23. The method of any of claims 17-20, wherein the stimulationsignal has a peak amplitude ranging between about 0.01 mA and about500.0 mA.
 24. A method for at least one of reducing the pH of gastricacid in a stomach of a patient and reducing an amount of gastric acidproduced in the patient's stomach, comprising: providing an hermeticallysealed implantable electrical pulse generator configured to provide atleast one electrical stimulation pulse regime effective to at least oneof reduce the pH of gastric acid and reduce the amount of gastric acidproduced in the patient's stomach; providing at least a firstimplantable medical electrical lead configured for implantationadjacent, around or in a selected electrode stimulation site, theelectrode stimulation site comprising at least one of the stomach, thevagus nerve, the plexus on the anterior superior and/or the anteriorinferior pancreaticoduodenal arteries, the plexus on the inferiorpancreaticoduodenal artery, the plexus on the jejunal artery, thesuperior mesenteric artery and plexus, the plexus on the gastroepiploicarteries, the celiac ganglia and plexus, the splenic artery and plexus,the left lesser thoracic splanchic nerve, the left greater thoracicsplanchic nerve, the principal anterior gastric branch of the anteriorvagal trunk, the left gastric artery and plexus, the celiac branch ofthe anterior vagal trunk, the anterior vagal trunk, proximal, distal orportions between the proximal and distal portions of the vagus nerve,the hepatic branch of the anterior vagal trunk, the right and/or leftinferior phrenic arteries and plexus, the anterior posterior layers ofthe lesser omenium, the branch from the hepatic plexus to the cardia viathe lesser omenium, the right greater thoracic splanchic nerve, thevagal branch from the hepatic plexus to the pylorus, the right gastricartery, the plexus and the intestine, and branches or portions thereof,the first lead comprising proximal and distal ends and at least oneelectrode; implanting the first lead in tissue of the patient adjacent,around or in the selected electrode stimulation site; operablyconnecting the proximal end of the at least first lead to theimplantable pulse generator; implanting the implantable pulse generatorwithin the patient; and delivering electrical stimulation pulses fromthe implantable pulse generator to the selected electrode stimulationsite through the at least first lead and electrode, the pulses beingprovided in accordance with the electrical stimulation pulse regime toat least one of reduce the pH of the gastric acid and reduce the amountof gastric acid produced by the patient's stomach.
 25. The method ofclaim 24, wherein the at least first lead is selected from the groupconsisting of an intramuscular lead, a unipolar lead, a bipolar lead, atri-polar lead, a quadrapolar lead, and a multi-polar lead.
 26. Themethod of claim 24, wherein the at least first lead is selected from thegroup consisting of a beam steering lead comprising multiple electrodesand a lead comprising multiple electrodes disposed in an areal patternon a planar or curved surface.
 27. The method of claim 24, wherein theat least first lead is selected from the group consisting of a cufflead, a paddle lead, a tined lead, a lead having an active fixationdevice or member disposed thereon, attached thereto or forming a portionthereof.
 28. The method of claim 24, wherein the at least first lead isselected from the group consisting of a suture sleeve, a barb, a helicalscrew, a hook and a tissue in-growth mechanism.
 29. The method of claim24, wherein the at least first lead further comprises one or moreelectrodes configured to operate in conjunction with an electricallyconductive portion of the implantable pulse generator acting as anindifferent electrode.
 30. The method of claim 24, further comprisingproviding, implanting, operably connecting and delivering electricalstimuli from a second implantable medical electrical lead configured forimplantation adjacent, around or in at least one of the stomach, thevagus nerve, the plexus on the anterior superior and/or the anteriorinferior pancreaticoduodenal arteries, the plexus on the inferiorpancreaticoduodenal artery, the plexus on the jejunal artery, thesuperior mesenteric artery and plexus, the plexus on the gastroepiploicarteries, the celiac ganglia and plexus, the splenic artery and plexus,the left lesser thoracic splanchic nerve, the left greater thoracicsplanchic nerve, the principal anterior gastric branch of the anteriorvagal trunk, the left gastric artery and plexus, the celiac branch ofthe anterior vagal trunk, the anterior vagal trunk, proximal, distal orportions between the proximal and distal portions of the vagus nerve,the hepatic branch of the anterior vagal trunk, the right and/or leftinferior phrenic arteries and plexus, the anterior posterior layers ofthe lesser omenium, the branch from the hepatic plexus to the cardia viathe lesser omenium, the right greater thoracic splanchic nerve, thevagal branch from the hepatic plexus to the pylorus, the right gastricartery, the plexus, and the intestine, or branches or portions thereof,wherein the second lead comprises proximal and distal ends and at leastone electrode.
 31. The method of claim 30, further comprising deliveringthe electrical pulses through tissue disposed between the electrodeslocated on the first and second leads.
 32. The method of claim 24,further comprising providing a lead extension, operably connecting samebetween the proximal end of the at least first lead and the implantablepulse generator, and delivering the electrical stimulation pulsesthrough the lead extension.
 33. The method of claim 24, wherein thefirst lead is selected from the group consisting of a lead comprising alead body less than about 5 mm in diameter, a lead comprising a leadbody less than about 1.5 mm in diameter, a lead having a lead bodycomprising polyurethane or silicone, a lead comprising electricalconductors disposed within the body thereof and extending between theproximal and distal ends of the lead wherein the conductors are formedof coiled, braided or stranded wires, and a lead comprising at least onering electrode, at least one coiled electrode, at least one buttonelectrode, at least one electrode formed from a portion of wire, a barbor a hook, a spherically-shaped electrode, and a helically-shapedelectrode.
 34. The method of claim 24, wherein an inter-electrodedistance of the first lead is selected from the group consisting ofabout 1 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm,about 7 mm, about 8 mm, about 9 mm, about 10 mm, about 12 mm, about 14mm, about 16 mm, about 18 mm, about 20 mm, about 25 mm, and about 30 mm.35. The method of claim 24, wherein the at least one electrode of thefirst lead has an electrode surface area ranging between about 1.0 sq.mm and about 100 sq. mm, between about 2.0 sq. mm and about 50 sq. mm,or between about 4.0 sq. mm and about 25 sq. mm.
 36. The method of claim24, wherein the distance between the proximal and distal ends of the atleast first lead is selected from the group consisting of less thanabout 4 inches, about 4 inches, about 6 inches, about 8 inches, about 10inches, about 12 inches, about 14 inches, about 16 inches about 18inches, about 20 inches and more than about 20 inches.
 37. The method ofclaim 24, wherein the implantable pulse generator comprises anelectronic circuitry architecture selected from the group consisting ofa microprocessor-based architecture, a logic architecture and a statemachine architecture.
 38. The method of claim 24, further comprisingproviding an external programming unit and effecting telemetriccommunication between the programming unit and the implantable pulsegenerator.
 39. The method of claim 24, wherein the implantable pulsegenerator further comprises at least one of a primary battery powersource and a secondary battery power source.
 40. The method of claim 24,wherein the implantable pulse generator is configurable so as to permitat least one of the frequency, rate, amplitude, phase, width andmorphology of the pulses generated and delivered thereby to be variedprogrammably by a user.
 41. The method of claim 24, wherein the at leastfirst lead is configured for percutaneous introduction and implantationwithin the patient.
 42. The method of claim 24, wherein the implantablepulse generator and the at least first lead are capable of generatingand delivering electrical pulses having frequencies ranging betweenabout 50 Hz and about 100 Hz, between about 10 Hz and about 250 Hz, andbetween about 0.5 Hz and about 20,000 Hz.
 43. The method of claim 24,wherein the implantable pulse generator and the at least first lead arecapable of generating and delivering electrical pulses having amplitudesranging between about 1 Volt and about 10 Volts, between about 0.5 Voltsand about 20 Volts, and between about 0.1 Volts and about 50 Volts. 44.The method of claim 24, wherein the implantable pulse generator and theat least first lead are capable of generating and delivering electricalpulses having pulse widths ranging between about 180 microseconds andabout 450 microseconds, between about 100 microseconds and about 1000microseconds, and between about 10 microseconds and about 5000microseconds.
 45. The method of claim 24, wherein the implantable pulsegenerator and the at least first lead and at least a second lead arecapable of generating and delivering electrical pulses having varyingspatial or temporal phases.
 46. The method of claim 24, furthercomprising delivering a drug to the patient.
 47. The method of claim 46,further comprising providing, implanting and activating an implantabledrug pump for providing the drug to the patient.
 48. The method of claim24, further comprising providing at least one sensor to sense a physicalcondition, and adjusting the stimulation regime or parameters based onthe sensed condition.